title: The eIF2α/ATF4 pathway is essential for stress-induced autophagy gene expression.
abstract: In response to different environmental stresses, eIF2α phosphorylation represses global translation coincident with preferential translation of ATF4, a master regulator controlling the transcription of key genes essential for adaptative functions. Here, we establish that the eIF2α/ATF4 pathway directs an autophagy gene transcriptional program in response to amino acid starvation or endoplasmic reticulum stress. The eIF2α-kinases GCN2 and PERK and the transcription factors ATF4 and CHOP are also required to increase the transcription of a set of genes implicated in the formation, elongation and function of the autophagosome. We also identify three classes of autophagy genes according to their dependence on ATF4 and CHOP and the binding of these factors to specific promoter cis elements. Furthermore, different combinations of CHOP and ATF4 bindings to target promoters allow the trigger of a differential transcriptional response according to the stress intensity. Overall, this study reveals a novel regulatory role of the eIF2α-ATF4 pathway in the fine-tuning of the autophagy gene transcription program in response to stresses.
authors.affiliation: INRA, UMR 1019 Nutrition Humaine, Centre de Clermont-Ferrand-Theix, F-63122 Saint Genès Champanelle, France and Université Clermont 1, UFR Médecine, UMR 1019 Nutrition Humaine, Clermont-Ferrand, France.
authors.forename: Wafa
authors.initials: W
authors.lastname: B'chir
authors.forename: Anne-Catherine
authors.initials: AC
authors.lastname: Maurin
authors.forename: Valérie
authors.initials: V
authors.lastname: Carraro
authors.forename: Julien
authors.initials: J
authors.lastname: Averous
authors.forename: Céline
authors.initials: C
authors.lastname: Jousse
authors.forename: Yuki
authors.initials: Y
authors.lastname: Muranishi
authors.forename: Laurent
authors.initials: L
authors.lastname: Parry
authors.forename: Georges
authors.initials: G
authors.lastname: Stepien
authors.forename: Pierre
authors.initials: P
authors.lastname: Fafournoux
authors.forename: Alain
authors.initials: A
authors.lastname: Bruhat
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000235:genetics*; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020218:Response Elements; D000071456:Sequestosome-1 Protein; D051742:Transcription Factor CHOP / Q000378:metabolism; D015533:Transcriptional Activation; D015854:Up-Regulation; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D051701:Activating Transcription Factor 4; D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids; D015852:Eukaryotic Initiation Factor-2; D006360:Heat-Shock Proteins; D017346:Protein Serine-Threonine Kinases; D000071456:Sequestosome-1 Protein; D051742:Transcription Factor CHOP; D019892:eIF-2 Kinase; C101343:Sqstm1 protein, mouse; C070634:Eif2ak4 protein, mouse